Misfolding and aggregation of some specific proteins is a hallmark of a variety of neurodegenerative disorders, including but not limited to Alzheimer's Disease (AD) and frontotemporal dementia. Attention and research has focused primarily on deposition of amyloid-β (Aβ) in senile plaques, although aggregation of pathological tau protein in neurofibrillary tangles also plays an important role in disease progression (Ballatore C. et al., Nat Rev Neurosci 2007, 8, 663-672).
Tau is a microtubule-associated protein. In AD, tau undergoes several changes to a pathological state. Tau can be abnormally folded and phosphorylated resulting in the generation of neurofibrillary tangles toxic to neurons. In AD, amyloid accumulation in the brain can occur decades before the beginning of symptoms such as memory loss and personality change. Current data suggest that Aβ pathology emerges prior to tau pathology, but may accelerate toxic neurofibrillary tangle formation. At best however, anti-Aβ immunotherapy only slightly decreases tau pathology and often does not affect the level of pathological tau at all. Moreover, pathological tau burden in the brains of patients with mild to moderate AD plays an important role in disease progression.